Metabolic Diseases Branch

Endocrine Signaling and Oncogenesis Section

William F. Simonds, M.D., Section Chief

The Endocrine Signaling and Oncogenesis Section studies the genetics and pathogenesis of familial forms of hyperparathyroidism and parathyroid cancer. This work includes work on the biology of CDC73/HRPT2, a tumor suppressor gene whose inactivation has been implicated in parathyroid malignancy. In addition, the Section is studying the biology of a unique brain and endocrine tissue-specific G protein complex (GΒ5-R7 RGS). These studies may have important implications for our basic understanding of neoplasia and neuroendocrine signaling. Specific projects investigate the pathogenesis and clinical spectrum of familial isolated hyperparathyroidism (FIHP), parathyroid cancer, and the hyperparathyroidism-jaw tumor syndrome (HPT-JT). Approximately 15 percent of all affected by HPT-JT have parathyroid cancer, and nearly 10 percent of adult cases appear to be silent carriers. The trait links to the CDC73/HRPT2 locus at 1q25-q31. CDC73/HRPT2 is a tumor-suppressor gene, the inactivation of which is directly involved in predisposition to HPT-JT and parathyroid cancer.

Research in this Section also focuses on the G protein β5 complex, with regulator of G protein signaling (RGS) proteins. G protein β5 is a neuronally expressed, structurally divergent G protein β isoform which may be functionally specialized. In general, RGS proteins act as GTPase activating proteins targeting Gα subunits and thus can help turn off G protein signaling. Recent evidence suggests, however, that certain RGS proteins can also function as signal transducers or effectors in their own right. G β5 forms a tight complex with RGS proteins of the R7 subclass in brain. Such complexes are expressed in the cell nucleus and cytoplasm (in addition to the plasma membrane). These observations are unexplained by current models of RGS. Researchers in the Section are investigating the function of the highly conserved Gβ5/ R7 RGS protein heterodimers in brain and neuroendocrine cells.

Signal Transduction Section

Lee S. Weinstein, M.D., Section Chief

The research interests of the Signal Transduction Section include:

1. The genetics and pathogenesis of parathyroid hormone resistance disorders that are caused by abnormal G protein signaling, including pseudohypoparathyroidism and Albright hereditary osteodystrophy (AHO).
2. The role of G protein signaling pathways in the central nervous system and in other metabolically active tissues in the regulation of energy and glucose homeostasis.
3. Genetics of familial hyperparathyroidism and other endocrine tumor syndromes.
4. Clinical research exploring the pathogenesis and novel therapies for multiple endocrine neoplasia type 1 and other familial and sporadic endocrine tumor syndromes.
   

Thyroid Tumors and Functional Thyroid Disorders

Joanna Klubo-Gwiezdzinska, M.D., Ph.D., M.H.Sc., Lasker Tenure Track Investigator, Acting Section Chief

Thyroid Tumors and Functional Thyroid Disorders Section focuses on clinical and translational studies aiming at appropriate risk stratification and therapy improving morbidity and mortality of patients with thyroid disorders. The pre-clinical work includes identification of genetic background of thyroid tumors, novel molecular targets for therapy of thyroid cancer and a comprehensive analysis of a cross-talk between cancer signaling pathways and metabolism. The goal of pre-clinical work is to translate its findings from bench to the bedside.